ABSTRACT Hypothesis: We hypothesize the diffusion properties and microstructure change across the entire length of the spinal cord during recovery from SCI. Also, we postulate that diffusion measurements and tissue sparing can be used to estimate sensorimotor function. In addition, we hypothesize that DTI is sensitive to regenerative interventions. Preliminary Data: Pilot studies have demonstrated the feasibility of obtaining DTI images of the injured and non-injured rat spinal cord using a high field (9.4T) small animal magnet. DTI images appear to follow expected patterns predicted by images obtained in chronic human SCI, with changes in diffusivity both at the injury site and in regions distant from the injury. Of particular note, reductions in diffusion appear in regions o fthe spinal cord distant from the injury site that correlate with histological data indicating cellular responses in neurons ofthe corresponding gray matter. Further, pilot data indicate that diffusion patterns are related to functional connectivity of the spinal cord, evidenced by correlations with spinal somatosensory evoked potentials (SSEPs). In separate studies, we have also demonstrated specific structural changes in the cervical dorsal hom of the rat spinal cord subjected to thoracic contusion injury and treated with stem cell grafts. These structural changes correlated with increased proliferation of pain fibers, which functionally resulted in the development of forelimb allodynia. We propose using this treatment paradigm, with well documented structural and functional changes, to test the diagnostic and prognostic abilities of DTI. Research Objectives: The overall goal of this project is to determine whether DTI can provide a non invasive imaging correlate of spinal cord structure and function following injury and regenerative therapies in a rat model of SCI. We plan to pursue this goal through three specific objectives. (1) Characterize region-specific changes in diffusivity during recovery from SCI. (2) Characterize functional correlates to DTI in the spinal cord during recovery from SCI. (3) Determine the sensitivity ofDTI to neuronal stem cell treatments following SCI. Our approach will use in vivo and ex vivo OTI to detemi.ine histological correlates during recovery from SCI. We will then determine the behavioral and electrophysiological functional correlates to DTI to histology and axonal morphometry. Lastly, we will determine the sensitivity of DTI to regeneration interventions with known changes in structure and function. The translational nature of this project is reflected by direct future application in humans if DTI is found to be able to detect histologically verifiable changes in morphology in the injured spinal cord. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans'Health Care: Spinal cord injury (SCI) constitutes one of the most devastating calamities that a person or their family can experience. With the United States currently engaged in several military efforts globally, SCI is likely to be an increasingly significant problem in the veteran population. This study will result in the validation of novel magnetic resonance imaging techniques (Diffusion Tensor Imaging, DTI) for monitoring the structural integrity and functional status of the spinal cord following an injury. We anticipate this information will prove vital to further understanding the pathology of SCI and establishing the use of DTI as an accurate, non-invasive diagnostic and prognostic tool. In addition, detailed information of the extent of injury and subsequent impact on sensorimotor function will prove invaluable in rehabilitative strategies involving pharmacological and physical therapies. We have focused in the last two years in the development and retention of a "team" approach to SCI treatment and imaging which uses experts in engineering (Dr Schmit), image acquisition and analysis (Dr Ulmer) and spinal cord interventions with stem cells (Dr Kurpad, Alexanian and Crowe). Dr Kurpad additionally is the Chief of the Neurosurgical Service at the Zablocki VA and has a strong interest in the clinical care of patients with SCI. This commitment to SCI clinical care and research is additionally reflected by his research support from the BL R&D MERIT Review Program. The presence of this "team" and the promising preliminary data that have culminated in five publications this year are expected to generate definitive data that can be translated successfully for the care of Veterans with SCI.